五种典型力场对气相中不同末端氨基酸的表现.docx
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五种典型力场对气相中不同末端氨基酸的表现.docx
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五种典型力场对气相中不同末端氨基酸的表现
Performancesoffiverepresentativeforcefieldsongaseousaminoacidswithdifferenttermini
XinChen1,ZijingLin1,2*
1HefeiNationalLaboratoryforPhysicalSciencesatMicroscale&CASKeyLaboratoryofStrongly-CoupledQuantumMatterPhysics,UniversityofScienceandTechnologyofChina,Hefei230026,China
2KeyLaboratoryofMaterialsPhysics,InstituteofSolidStatePhysics,ChineseAcademyofSciences,Hefei230031,China
*Correspondingauthor:
ZijingLin;Tel+86-551-63600345;Email:
zjlin@
Abstract:
Thereisagrowinginterestinthestudyofstructuresandpropertiesofbiomoleculesingasphase.Applicationsofforcefieldsarehighlydesirableforthecomputationalefficiencyofthegasphasestudy.Tohelptheselectionofforcefields,theperformancesoffiverepresentativeforcefieldsforgaseousneutral,protonated,deprotonatedandcappedaminoacidsaresystematicallyexaminedandcompared.Thetestedpropertiesincluderelativeconformationalenergies,energydifferencesbetweencisandtransstructures,thenumberandstrengthofpredictedhydrogenbonds,andthequalityoftheoptimizedstructures.TheresultsofBHandHLYP/6-311++G(d,p)areusedasthereferences.GROMOS53A6andENCADSarefoundtoperformpoorlyforgaseousbiomolecules,whiletheperformanceofAMBER99SB,CHARMM27andOPLSAA/Larecomparablewhenapplicable.Consideringthegeneralavailabilityoftheforcefieldparameters,CHARMM27isthemostrecommended,followedbyOPLSAA/L,forthestudyofbiomoleculesingasphase.
Keywords:
Conformation,RelativeEnergies,CorrelationCoefficient,HydrogenBond,MolecularMechanics
1.Introduction
Empiricalmolecularforcefieldsareroutinelyusedintheinvestigationsofstructure-property-activityrelationshipsinbiologicalsystemsasthecomputationalcostoftreatingthesesystemsquantummechanicallyisoftenunbearablyhigh.Theforcefieldsareingeneralderivedbyfittingparameterstodatafromquantumchemicalcalculationsorexperimentsonmodelmoleculesthatmaymimicthepropertiesoftheinterestedbiomolecules.Fittingtheexperimentaldataforthecondensed-phaseenvironmentisemphasized.Thisisreasonableasthestructuresandpropertiesofbiomoleculesinsolutionorcondensed-phaseenvironmentareofthemostinterest.However,thisalsomeansthattheaccuracyoftheforcefieldtopredicttherelevantpropertiesinthegasphaseissacrificed.Italsorepresentsaparadoxinthefittingphilosophyasthequantumchemistryresultsforthegasphaseareindispensiblefortheforcefieldparameterization[1].
Thelimitationofforcefieldsforthegasphasestudyisoftendismissedasirrelevant.Indeed,impressiveprogresseshavebeenmadeinutilizingforcefieldsforthestudyofbiologicalsystems,e.g.,simulatingtheproteindynamics[2-7].However,thecontradictioninherentinthefittingphilosophyhassomeseriousconsequences.Asthereisnorigorouswaytodeterminetheoptimalparameterset,manyforcefieldvariantsareproposedbasedondifferentemphasesofthefittingtargets.AMBER[8],CHARMM[9],ENCAD[10],GROMOS[11]andOPLSAA[12]areexamplesofforcefieldsthatarewidelyinuse.Therehavebeennumerousarticlesandreviewsdiscussingabouttheperformancesofmodernforcefieldsforbiomoleculesinsolutionorcondensed-phaseenvironment[4,5,7,8,13].Thesestudiesshowclearlythataproperchoiceoftheforcefieldisdependentontheresearchsubjectofinterest.
Comparativestudiesoftheforcefieldsarecrucialfortheproperselectionofforcefield,butsystematicstudiesontheperformancecomparisonforobjectsingasphasearerare.Thelimitationofforcefieldsforthegasphasestudyhadbeendismissedasirrelevant.However,thereisagrowinginterestandeffortinstudyingthegaseousbiomoleculesthatarefreefromthecomplicationcausedbythecomplexsolute-solventinteractions[14-20].Consequently,asystematiccomparisonoftheperformancesoftheforcefieldsforbiomoleculesingasphaseisbecomingincreasinglymeaningful.Thecomparisonishelpfulforthechoiceofforcefieldthatisnecessaryformanygasphasestudies,e.g.,MDrunsofbiomoleculewithabout100ormoreatoms.Evenwhentheforcefieldisusedasapre-screeningtool,thecomparativestudyisalsohelpfulforavoidingusingaforcefieldthatprovidesmisguidedinformationaboutthepotentialenergysurface.Moreover,thecomparativestudyisthestartingpointforlearningtheaccuraciesofthestate-of-the-artforcefieldsforthegasphasestudy.Suchinformationisalsohelpfulforknowinghowmuchtheimprovementofforcefieldisrequiredtoprovideresultsforthegasphasestudywithadesirableaccuracy.Theinformationisusefulforguidingthefuturedevelopmentofforcefield.
Thechoiceoftestingobjectsinthisstudyisguidedbysomegeneralconsiderations.First,proteinforcefieldparametersaremainlydeterminedbyfittingdataforcappedalanine,cappedglycineandcappedproline[13,14,21-24].Otheraminoacidresiduesplayonlyminorroleintheparameterdetermination.Theapproachseemstoworkwellforproteinsincondensed-phaseenvironment[2,5,7,14,18],partlyduetothefactthatmostattentionispaidtothebackbonestructures.Forshortpeptides,theinfluenceofthesidechainonthebackboneisexpectedtobesubstantialandhowwelltheforcefieldsworkforotheraminoacidresiduesrequiresdetailedexaminations.Second,theoverallinfluenceoftheaminoandcarboxylterminalgroupsisrelativelysmallforlargemoleculessuchasproteins,butthecorrespondinginfluenceforshortpeptidescanbesignificant.Shortpeptidesareaclassofbiomoleculeswithimportantbiologicalandphysiologicalroles.Theyarealsothestartingpointforthepeptide-baseddrugdesignstudy[25].Theaminoandcarboxylgroupsareimportantintheforcefieldperformancestudy.Third,protontransferiscriticallyimportantfornumerousbiologicalprocesses.Itisthereforehighlymeaningfultoincludetheprotonatedaminogroupanddeprotonatedcarboxylgroupinthetestingobjectset.Therefore,theforcefieldperformancesaretestedhereforalargenumberofgaseousaminoacidswithnatural,protonated,deprotonatedandcappedtermini.
Forcefieldsaremeanttoreproducethestructuralandenergeticinformationobtainedbyexperiments,preferably,orquantumchemistrycalculations.Astheexperimentaldataareverylimited,comparingtheforcefieldswiththequantumchemistrycalculationsaremoreconvenientand,possibly,statisticallymoremeaningful.Infact,thebestonemayhopeforisthattheresultsbyaforcefieldareclosetothatbyquantumchemistrycalculations.Therefore,thequantumchemistryresultsmaybeusedasthereferencestotesttheperformancesofdifferentforcefields.Noticethatthereareanumberofquantumchemistrymethodsandthedensityfunctionaltheory(DFT)basedapproachisfavoredforitsaccuracyandcomputationalefficiency.AmongtheDFTvariantstestedforallneutral,protonatedanddeprotonatedaminoacids,theBHandHLYP/6-311++G(d,p)methodhasbeenshowntoproducethebestenergeticresultsstatistically[26].WhenbenchmarkedwiththeCCSD/6-311++G(d,p)results,thestatisticalqualityoftheBHandHLYPresultsisevenslightlybetterthanthatoftheMP2computations[26].Consequently,theforcefieldsarebenchmarkedwiththeBHandHLYPresults.
2.Method
Theabilitiesoffiveforcefields,AMBER,CHARMM,ENCAD,GROMOSandOPLSAA,tomimicthequantumchemistry,BHandHLYP/6-311++G(d,p)energeticandgeometricresultsaretestedwithfourrepresentativeproperties:
1)relativeconformationalenergies,2)energydifferencesbetweencisandtransstructures,3)numberofpredictedhydrogenbonds(H-bonds),4)structuralsimilarityasmeasuredbytheroot-mean-square-difference(RMSD).Thefiveforcefieldshavevariousversionsofparameterizationsandtheirrelativelynewparameterizationsets,AMBER99SB[27],CHARMM27[21],GROMOS53A6[28],ENCADS[29],OPLSAA/L[30],areusedinthetest.
19naturallyoccurringaminoacidsincludingglycine(GlyorG),alanine(AlaorA),valine(ValorV),leucine(LeuorL),isoleucine(IleorI),asparagine(AsnorN),glutamine(GlnorQ),cysteine(CysorC),methionine(MetorM),serine(SerorS),threonine(ThrorT),proline(ProorP),tyrosine(TyrorY),tryptophan(TrporW),phenylalanine(PheorF),histidine(HisorH),lysine(LysorK),asparticacid(AsporD)andglutamicacid(GluorE)areconsideredinthetestingsetofthecurrentstudy.Fourterminusformsofaminoacids,natural,protonated,deprotonatedandcapped,areusedinthetesting.Incapedaminoacids,theN-andC-terminiarecappedwiththeacetylandN-methylaminegroups,respectively.Toillustrate,thestructuresofnatural,protonated,deprotonatedandcappedalaninearesketchedinFigure1.
Tobeofhighstatisticalsignificance,theconformationsoftheseaminoacidsareobtainedthoughsystematicsearchesbyconsideringallcombinationsofbondrotationaldegreesoffreedominthetrialstructuregenerations,asdescribedinliteratures[31].TheQMstructuresaredeterminedattheBHandHLYP/6-31G*level.Thenumbersofuniqueconformationsthusobtainedforthesemoleculesareshowninparenthesesasthefollowings.Fornatural,protonated,deprotonatedandcappedaminoacids,theyarerespectivelyAla(8,3,2,6),Asn(62,9,11,71),Asp(106,26,24,20),Cys(78,5,12,49),Gln(59,8,14,138),Glu(340,10,16,72),Gly(16,3,1,4),His(57,12,8,56),Ile(85,33,19,62),Leu(96,12,23,68),Lys(186,13,51,427),Met(172,15,31,190),Phe(31,10,8,32),Pro(20,6,7,10),Ser(52,12,19,49),Thr(71,12,7,52),Trp
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- 典型 力场 相中 不同 末端 氨基酸 表现
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